Composition for altering physiological processes of livestock and poultry and process of using same



Patented Feb. 13,- 1951 COMPOSITION FOR ALTERING PHYSIO- LOGICALPROCESSES OF LIVESTOCK AND POULTRY AND BROCESS USING SAME Charles W.Turner and Ezra P. Reineke, Columbra, Mo., assignors to American DairiesIncorporated, Kansas City, Mo., a corporation of Maryland, and TheQuaker Oats Company,

Chicago, 111., a corporation of New Jersey No Drawing. Application April9, 1945, Serial No. 587,444

- 19 Claims. I

This invention relates to improvements in altering and controllingcertain physiological processes in livestock and poultry by the additionto their ration of selected natural or synthetic estrogen-like chemicalcompounds known as diethylstilbestrol and its derivatives including itsesters and ethers; dihydrostilbestrol (hexestrol) as well as derivativesof the latter; and benzestrol, 2,4 di(parahydroxyphenyl 3-ethyl hexane).

In its broader aspects the invention comprises the addition to theration of livestock or poultry predetermined critical amounts of any oneof several natural or synthetic estrogen-like compounds includingdiethylstilbestrol or its derivatives, hexestrol, benzestrol, and othernatural or synthetic estrogens such as those indicated to accomplish theobjectives sought.

There is contemplated also in our invention the incorporation of thehormones and chemicals with salt and/or mineral mixtures of calcium,phosphorus and trace elements or other supplements fed to livestock andpoultry in such manner and amount as to be mixed with part or all of thefeed concentrate mixture or to be fed as a separate addition to theration. In such cases the total supplement either separately or whenmixed with the feed concentrate mixture should be such as to provide theadministration of the hormones and chemicals within the range of dailyintake specified in the examples hereinafter set forth.

The favorable physiological efiects which may be obtained by addingthese materials to the ration in milk producing animals such as cows,and goats includes general body growth and the growth of the mammarygland (the udder) and when sufiicient secretory tissue has developed,the initiation and maintenance of milk secretion. These favorableefiects are obtained by the action which the materials have upon theanterior pituitary hormonesinfiuencing growth and other productiveprocesses, as well as upon the genital tissues concerned. Thus, in dairyanimals in which normal reproductive processes fail, the addition tothese materials causes the stimulation of the growth of the udder,initiation of and an increase in the commercial quantities of milkproduced. In lactating animals controlled use of the materials atintervals during the lactating period tends to maintain and in somecases increase the normal lactation level. The amount or level of oraladministration is critical and previous methods of periodic subcutaneousinjection or implantation, because of the critical nature of the dosage,have not produced satisfactory efiects due to inequality of the level ofhormones in the blood. By the oral method the rate of absorption fromthe gut in poultry and livestock is more uniform. Also, proper use ofthe material in poultry maintains the appetite of the growing birds andincreases the mobilization of blood lipids and their deposition asadipose tissue. It also increases serum calcium, increases thedeposition of fat and generally improves the market grade of the birds,as well as the quality of the tissue.

In laying birds the appetite, secretions of the anterior pituitary, andsecretions of the oviduct are all stimulated, increasing and maintaininga high rate of egg production besides accelerated mobilization of bloodlipids and increasing serum calcium. and other physiological processesrelated to egg production.

In connection with compounds used accordin to the teachings of ourco-pending application Serial No. 501,988, filed September 11, 1943, nowPatent No. 2,385,117, issued September 18, 1945, it is contemplated thatthe estrogen and estrogen like materials herein disclosed may be usedtherewith to further stimulate growth, maintain egg production throughthe favorable action on the appetite exemplified in feed consumption,and the mobilization of blood lipids, calcium, and the action on thesecretions of the oviduct associated with egg production.

Likewise these synthetic estrogens may be used to augment or supplementcompounds for inhibiting the endocrine function of the thyroid gland inanimals and poultry disclosed in our co-pending application Serial No.513,496, filed December 8, 1943, now Patent No. 2,438,353, issued March23, 1948. By simultaneous use of these materials the appetite of thefowls and animals is maintained or increased, the metabolism decreased,and the deposition of body fat accelerated to a greater extent than ispossible by either method alone.

It is known that the oral efiectiveness of synthetic estrogens such asdiethylstilbestrol and its derivatives varies to a great extent on thetype. of digestive system in the animal in which the treatment ispracticed. In animals having a simple digestive system some naturalestrogens and diethylstilbestrol are efiective when administered orally.In ruminant animals and in fowls it has been found that the naturalestrogens and diethylstilbestrol are relatively ineffective when givenorally so the beneficial efiects cannot be economically obtained. It hasbeen discovered that the phenolic hydroxyl groups of diethylstilbestrolwhen etherilied protect the essentialstructure of the material so whenfed to ruminants and birds the material has a much greater pmrsiologicalactivity and efiect, therefore it is desirable that these more potentpreparations be used when the materials are to be administered toruminants or fowls. Many esters of diethylstilbestrol such asdipropionate, dibenzoate, or dipalmitate have been prepared, as well asethers including the monoand dimethyl or the monoor diethyl compounds.Of these thedimethyl ether of diethylstilbestrol, in so farasexperimental observations have shown, proves to be most effective inbirds and ruminants. The effective dosage range for favorable efiectswill be indicated in terms of the dimethyl ether, al-

though it is not intended to limit the invention solely to the use ofthis particular material since any estrogen which is orally efiective ina given species and at the proper dosage will produce the desiredresult. As typical examples of the results which were obtainedfromexperiments which have been made upon live animals, the followingwill indicate the efiectiveness of the compounds.

Example I As a premise for the examples which are to follow it had beenobserved that a suitable dose of diethylstilbestrol administeredsubcutaneously resulted in growth of the udder in dairy cows and goatsand stimulation of the anterior pituitary to increase lactogenic hormonesecretion. If the material was administered in excessive amounts, evenestablished lactation was inhibited. Injection subcutaneously of 0.25mg. of diethylstilbestrol into 50-100 lb. goats stimulated the growth ofthe udd'er and eventual lactation. On the other ha .d, if 1.0 mg. ofdiethylstilbestrol is injected daily into 50-100 lb.

lactating goats, milk secretion is slightly depressed, 2.0 mg.moderately depressed lactation and 4.0 mg. seriously depressedlactation. In fact after ten days of administration, lactationpractically ceased on the latter dose, however, after stopping orgreatly reducing the amount injected, milk secretion returned to aboutthe preinjection level or above.

As the effect upon lactation is a good measure of potency ofdiethylstilbestrol, a comparison was made of the efiectiveness ofsubcutaneous administration as compared with oral administration of thedifferent compounds. By this comparison the administration ofdiethylstilbestrol orally to the ruminant (dairy goat) is only about 1%as effective as when administered by injection. In other words, where4.0 mg. of diethylstilbestrol injected subcutaneously will greatlyinhibit lactation in ten days of treatment, 400 mg. or more are requiredto obtain a like efiect when given orally. When, however, 100 mg. dailyof dimethyl ether of diethylstilbestrol is fed to lactating goats, adecrease in lactation comparable to the efiect produced with 400 mg. or

more of diethylstilbestrol is obtained, indicating that the dimethylether is about four times as mals. To accomplish the desired favorablephysiological effects by use of the dimethyl ether compound which is tostimulate the growth of the mammary gland (the udder) in goats from to100 lbs. body weight, 5 to 50 mg. daily per 100 lbs. body weight wastedin capsules. The preferred method is to add the hormone at the rate of10 to 100 mg. per kilogram of grain or concentrate mixture to be fed.at. the rate of about 0.5 kg. per 100 lbs. body weight of animal dailyor in other proportions provided the range in total daily intake is thesame. When the growth of the udder had been stimulated and milksecretion initiated the amount of the dimethyl ether compound wasreduced to about onehalf, fed separately or as a constituent of thegrain feed for stimulation and maintenance of lactation. I

It should be noted that amounts of the hormone in this and the followingexamples less than the specified dosage range will be harmless so thatin practice only maximum amounts need be considered critical. However,amounts near or below the minimum specified have been observed to havediminishing favorable 'eiIects.

For dairy cows weighing1000 lbs. it was necessary to feed 50 to 500 mg.daily to stimulate the growth of the cow's udder. As a component part ofthe feed this compound was added at the rte of 10 to 100 mg. per kg. ofthe grain concentrate mixture fed at the rate of about 5 kg. per day orin other proportions providedthe range in total daily intake is thesame. When the dairy animals were stimulated to maximum milk productionthe dimethyl ether in the feed was reduced about one-half for continuedstimulation and for maintenance of lactation. Tests were made withdiethylstilbestrol and its derivatives used as a supplement withartificialthyroprotein produced according to co-pending applicationspreviously referred to. ,The diethylstilbestrol compounds were employedto stimulate the total growth of the udder while the artificialthyroprotein was .used toiaugment the rate of growth as a result of thefavorable effects of thyroxine' dimethyl ether" compound wereadministered daily per lbs.. body weight. Supplementing this there wasadministered protamone or an iodinated thyroprotein of standard potencycontaining 3% thyroxine and this latter compound was administered inamounts ranging from 0.3 to 2 gm., a typicaldosage or the combinedmaterials being 10 to 100 mg. of the first compound and 0.6 to 4 gms. ofthe latter per kg. of the grain concentrate mixture and fed at the rateof about 0.5 kg. per 100 lbs. body weight daily or in other proportionsprovided the range in total daily intake is the same. When growth of theudder of the cow was stimulated and milk secretion initiated, the amountof the dimethyl ether compound was reduced about one-half administeredeither separately or as a component part of the grain concentratemixture, while the feeding of protamone in the grain concentrate mixturecontinued at the original level.

For dairy cows weighing 1000 lbs. (and for other weightsproportionately) it is recommended to feed from 50 to 500 mg. daily ofdimethyl ether of diethylstilbestrol plus 5 to 15 gms. of protamonedaily to obtain the desired stimulation both of the cow's growth andudder growth. These compounds are preferably added as a'com Example IIThe administration of diethylstilbestrol by injection or by implantationof pellets has been found effective in suitable amounts for stimulatingthe appetite and growth rate, in acting upon the secondary sex tissuessuch as the oviduct, and upon the character of producing increases inthe blood lipids and calcium as well as the deposition of body fatcharacteristic of sexual maturity. However, huge doses of this chemicalcompound were required when administered orally to fowls.

The range of dosage indicated in the following examples are given interms of the total growing, fattening or egg laying feed mixtures. If itis desirable to feed the food composition described herewith as a partof the total ration or as a supplement to the ration the amounts ofactive substance added would be increased in proportion to the ratiowhich the feed composition containing the specified ingredients bears tothe total feed consumption, thus providing the same range in total dailyintake of the critical substances.

when dimethyl ether diethylstilbestrol was fed to young chickens at therate of 1 gm. per 10 kg. (or 0.1 gm. per kg.) of complete feed or at thelevel of 0.01% of the total starting ration, the weight of the oviductwas increased four times, body weight was increased, and the thyrotropichormone of the anterior pituitary was significantly increased. At thesame time the deposition of fat on the carcass was very pronounced.Tests of various kinds indicate that the dimethyl ether compound is fromsix to ten times as effective when administered orally to fowls as thefree compound. To accomplish the favorable physiological effects ofdiethylstilbestrol in fowls, the dimethyl ether of diethylstilbestrol isadded to the complete poultry food at the rate of 0.5 to 4 gm. per 10kg. of feed, (or 0.05 to 0.4 gm. per kg.), or at the rate of 0.005% to0.04% of the feed. Optimum results appear at about the level of 0.01% ofthe feed for the most rapid growth, feed consumption and rapidfattening. During the period'of growth best results are obtained byadding the dimethyl ether compound to the complete ration at the rate of0.5 to 4 gm. per-10 kg. of feed (or 0.05 to 0.4 gm. per kg), plusprotamone or an iodinated protein of standard potency at the rate of .9to 10 gms. per 10 kg. of feed or at the rate of 0.005% to 0.04% of theformer and 0.009% to 0.10% of the latter with respect to the totalration. In place of protamone any thyroxine or thyroglobulin containingpreparation with equivalent thyroxine potency may be substituted. Theamount of thyroxine would comprise from 0.0003% to 0.003% of the foodconsumed by the growing bird.

In laying hens the dimethyl ether compound is fed at the rate of 0.05gm. to 0.4 gm. per kg. (or 0.005% to 0.04%) of feed to maintain theappetite, increase the blood lipids and have the other favorableinfluences noted. By feeding the dimethyl ether compound at the rate of05 gm. to 0.4 gm. per kg. of feed to maintain uniformity of itsfavorable effect upon eg production, plus I protamone (containing 3 thyroxine) at the rate of 0.9 to 4 gms. per 10 kg. of feed (or 0.09 to 0.4

gm. per kg.) simultaneously, tht beneficial effects of each constituentare additive and increase the benefit of each substance fed alone.

From the above it will be observed that to a complete laying feed shouldbe added 0.005% to 0.04% of the dimethyl ether compound and. 0.009% to0.04% of protamone containing 3% of thyroxine. In place of protamone,thyroxine or thyroglobulin containing preparation with equivalentpotency may be substituted at the rate of 0.0003% to 0.0012% of the feedconsumed.

Example III In the fattening of fowls of any age, but especially in thecase of broilers the most rapid fattening effect has been obtained bythe combined use of the dimethyl ether compound at the level suggestedin Example 11, and thiouracil or thiourea in amounts suggested in ourprevious application or any other anti-thyroid or goitrogenic drug inamounts suflicient to produce an equivalent suppression of the thyroidsecretion.

In practice there are several variations in the feed procedure whichwill favorably influence the rate of growth and the final quality of thecarcass.

1. During the growth period the dimethyl ether compound should be addedto the complete ration at the rate of 0.5 to 4 gms. per 10 kg. of feed,then during the fattening period of variable duration add 0.1 gm. to 1.5gm. ofthiouracil, thiourea or related compounds per 10 kg. of feed.

2. During the growing period the dimethyl ether of diethylstilbestrol isadded to the growing ration at the rate of 0.5 to 4 gms. per 10 kg. offeed plus protamone (containing 3% of thyroxine) at the rate of 0.9 to10 gms. per 10 kg. of feed or thyroxine in equivalent amount. Thenduring the fattening period of variable duration add 0.1 gm.'to 1.5 gm.of thiouracil, thiourea or related compounds per 10 kg. of feed and omitthe protamone or thyroxine.

3. During the growing period the dimethyl ether compound should be addedto the growing ration at the rate of 0.5 to 4 gm. per 10 kg. of feedplus protamone (containing 3% thyroxine) at the rate of 0.9 gm. to 10gms. per 10 kg. of feed or thyroxine in equivalent amounts. Then duringthe fattening period remove the protamone or thyroxine but continue thedimethyl ether compound.

Example IV For all livestock, meat and fur animals including rabbits,foxes, experimental animals, swine, horses, etc. having simple stomachs,estrogen and the simple compounds of diethylstilbestrol, hexestrol, orbenzestrol have been found more effective than the derivativesmentioned. With such a variety of effective products and with so aun -447 be noted that less than the minimum indicated is harmless to theanimals or poultry and that the maximum'chosen ineach case-is thecritical amount which should-be closely governed and controlled.

Having thus described our invention, we claim:

1. A composition'ror' stimulating the growth of the 'malnrnarylglandsand secretion of lactogemc hormone or the'anterior pituitary to initiateand maintain-milk secretion in livestock comprising a day's normalconcentrate grain ration to which has been added mg. to 50 mg. ofdimethyl ether or diethylstilbestrol for each 100 lbs. of the animal'sweight.

2. A prooedure'for stimulating the growth of mammary glands of growncattle or livestock of similar size consisting of administering 50 mg.to 500 mg. of dimethyl ether of diethylstilbestrol and 5 gm. to gm.protamone having 5% myroxine potency per 1000 lbs. of body weight daily.

3. A procedureas in claim 2 wherein there is substituted for thedimethyl ether of diethylstilbestroi a synthetic estrogen of equalphysiological activity selected from the class consisting ofdiethylstilbestrol, esters of diethylstilbestrol, hexestrohethers ofhexestrol, esters of hexestrol, benzestrol, ethers or benzestrol, andesters of benzestrol. l

4. A procedurefor stimulating the secretion of the lactogenic hormone ofthe anterior pituitary and the initiation and maintenance of milksecretion in grown cattle or livestock of similar size comprisingadministering 25 mg. to 250 mg. of dimethyl ether of diethylstilbestroland 5 gm. to 15 gm; protamone having 3% thyroxine potency per 1000lbs.-'body weight daily.

5. A procedure as in claim 4 in which there is substitutedfor thedimethyl ether of diethylstilbestrol a synthetic estrogen of equalphysiological activity selected from the class consisting ofdiethylstilbestrol, esters of diethylstilbestrol, hexestrol, ethers ofhexestrol, esters of hexestrol, benzestrol,. ethersof benzestrol, andesters of benzestrol.

6. A composition for improving the feed consumption and growth rate ofpoultry consisting of a normal feed ration to each kg. of which has beenadded 0.05 gm. to-'0.4 gm. of dimethyl ether of diethylstilbestrol and/0.09 gm. to 1.0 gm. protamone containing 3% thyroxine.

7. A composition as in claim 6 in which there is substituted for thedimethyl ether of diethylstilbestrol a synthetic estrogen of equalphysiological activity selected from the class consisting ofdiethylstilbesterol, esters of diethylstilbesterol,

hexestrol, ethers of hexestrol, esters of hexestrol,

benzestrol, ethers of benzestrol, and esters of benzestrol. 0

8. A composition for improving the feed consumption and .-,g row th rateof poultry consisting of a normal 'feedration to each kg. vof which hasbeen added 0.05 gm. to 0.4 gm. of dimethyl ether of diethylstilbestroland 0.0025% to 0.2% of compounds of .thegroup of thiourea andthiouracil.

9. A composition for increasing and maintaining egg production andmarket grade of poultry, consisting of a normal feed ration to which hasbeen added-0.005%"to 0.04% of dimethyl ether of diethylstilbesterol and0.009% to 0.04% of protamone containing 3%of thyroxine.

10. A compositiohgas in claim 9 in which there is substituted .for-the.dimethyl ether of diethylstilbestr'ofa synthetic estrogen which willproduce equal physiological activity selected from the class consistingoi diethylstilbesterol, esters ofdiethylstilbest'erol,hexestrol,ethersofhexestrol, esters or hexestrol,}lcpenzestrol ethers of benzestrol and esters orbenzestrol. 1

11. A dosage procedure m vs ulating' the vgrowth or mammary "glands andthe secretion 01' lactogemc hormone or tne;anter1or pituitary inlivestock, comprising the'ste'ps ot adding to a normal concentrate grainration 0.001% to 0.01% of dimethy ether-oi diethylstilbesterol, andreeding the mixture at theaily rate of 0.5 kg. of said mixture per 100lbs. of bodyweight of the animal.

12. A procedure as in claim- 11 wherein there is substituted'ror thedimethyl ether of diethylstilbesterol a synthetic estrogen of equalphysiological activity selectedirom the class consisting ofdiethylstilbesterol, esters of diethylstilbesterol, hexestrol, ethers ofhexestrol, esters of hexestrol, benzestrol, ethers of benzestrol andesters or benzestrol.

13. A dosage procedure for stimulating the secretion of lactogenichormone of the anterior pituitary and maintaining milk secretioninlivestock comprising the steps of adding to a normal concentrate grainration 0.0005% to 0.005% of dimethyl ether of diethylstilbesterol, andfeeding the mixture at the many rate 01' 0.5 kg. per 100 lbs. bodyweight of the animal.

14. A procedure as .in claim13 wherein there is substituted for thedimethyl ether of diethylstilbesterol a synthetic estrogen-of equalphysiological activity selected from the class consisting ofdiethystilbesteroL-esters of diethylstilbesterol, hexestrol, ethers ofhexestrol, esters of hexestrol, benzestrol, ethers of benzestrol andesters of benzestrol.

15. A dosage procedure for stimulating the secretion of lactogenichormone of the anterior pituitary and maintaining milk secretion inlivestock, comprising the steps of adding to the normal concentrategrain ration 0.001% to 0.01% of dimethyl ether of diethystilbesterol and0.06% to 0.4% of protamone having 3% thyroxine potency, and feeding themixture at the daily rate of 0.5 kg. per 100 lbs. body weight of theanimal.

16. A dosage procedure' for stimulating the growth of mammary glands andthe secretion of estrogenic hormone of .the. anterior pituitary. to'

initiate and maintain secretion in livestock, comprising the steps ofadding to a normal concentrate grain ration 0.00,05% to 0.005% ofdimethyl ether of diethylstilbesterol and 0.06% to 0.4% of protomonecontaining 3% thyroxine, and

feeding the mixture at the daily rate of 0.5 kg;

per 100 lbs. body weight of the animal.

17. A procedure Ior stimulating and maintain v I ing milk secretion inlactating animals comprising the steps of orally administering dimethylether of diethylstilbesterol at the, daily rate of,

5 to mg. per lbs. of the animal's body .weight until maximum milkproduction is achieved, and thereafter. orally administering dimethylether of diethylstilbesterol at the daily rate of 2.5 to 25 mg. per 100lbs. of the animal's body weight. 1

18. A procedure as in claim 1'? wherein there is substituted for thedimethyl ether of diethylstilbesterol a'synthetic estrogen of equalphysiological activity selected from the group consisting ofdiethylstilbesterol, esters of diethylstilbesterol, hexestrol, ethers ofhexestrol, esters of hexestrol,

benzestrol, ethers of 'benzestrol and esters- 0t benzestrol. r

19. A procedure as in claim 1"! including the additional step ofadministering protamone contaming 3% thyroxine at the daily rate of 0.3to

2 gm. per 100 lbs; of the animals body weight.

CHARLES W. TURNER. EZRA P. REINEKE.

REFERENCES crrEn The following references are of record in the file ofthis patent:

Poultry Science/Jan. 1945, vol. XXIV, No. 1, 10

published by the Omcial- Journal of Poultry Science Assn., pages 91 and92.

Poultry Science, May 1944, vol. XXIII, No. 3, pages 249 to 251.

Manufacturing Chemist and Manufacturing Perlumer, June 1943. The ExtraPharmacopoeia" by Martindale, volume I, 22nd edition, 1941, pages 725 to728. Merck Index, 1940, page 196.

1. A COMPOSITION FOR STIMULATING THE GROWTH OF THE MAMMARY GLANDS ANDSECRETION OF LACTOGENIC HORMONE OF THE ANTERIOR PITUITARY TO INITIATEAND MAINTAIN MILK SECRETION IN LIVESTOCK COMPRISING A DAY''S NORMALCONCENTRATE GRAIN RATION TO WHICH HAS BEEN ADDED 5 MG. TO 50 MG. OFDIMETHYL ETHER OF DIETHYLSTILBESTROL FOR EACH 100 LBS. OF THE ANIMAL''SWEIGHT.